Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome.
Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS. Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5). In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both). In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.


The synthesis, characterisation and reactivity of 2-phosphanylethylcyclopentadienyl complexes of cobalt, rhodium and iridium.
2-Phosphanylethylcyclopentadienyl lithium compounds, Li[C(5)R'(4)(CH(2))(2)PR(2)] (R = Et, R' = H or Me, R = Ph, R' = Me), have been prepared from the reaction of spirohydrocarbons C(5)R'(4)(C(2)H(4)) with LiPR(2). C(5)Et(4)HSiMe(2)CH(2)PMe(2), was prepared from reaction of Li[C(5)Et(4)] with Me(2)SiCl(2) followed by Me(2)PCH(2)Li. The lithium salts were reacted with [RhCl(CO)(2)](2), [IrCl(CO)(3)] or [Co(2)(CO)(8)] to give [M(C(5)R'(4)(CH(2))(2)PR(2))(CO)] (M = Rh, R = Et, R' = H or Me, R = Ph, R' = Me; M = Ir or Co, R = Et, R' = Me), which have been fully characterised, in many cases crystallographically as monomers with coordination of the phosphorus atom and the cyclopentadienyl ring. The values of nu(CO) for these complexes are usually lower than those for the analogous complexes without the bridge between the cyclopentadienyl ring and the phosphine, the exception being [Rh(Cp'(CH(2))(2)PEt(2))(CO)] (Cp' = C(5)Me(4)), the most electron rich of the complexes. [Rh(C(5)Et(4)SiMe(2)CH(2)PMe(2))(CO)] may be a dimer. [Co(2)(CO)(8)] reacts with C(5)H(5)(CH(2))(2)PEt(2) or C(5)Et(4)HSiMe(2)CH(2)PMe(2) (L) to give binuclear complexes of the form [Co(2)(CO)(6)L(2)] with almost linear PCoCoP skeletons. [Rh(Cp'(CH(2))(2)PEt(2))(CO)] and [Rh(Cp'(CH(2))(2)PPh(2))(CO)] are active for methanol carbonylation at 150 degrees C and 27 bar CO, with the rate using [Rh(Cp'(CH(2))(2)PPh(2))(CO)] (0.81 mol dm(-3) h(-1)) being higher than that for [RhI(2)(CO)(2)](-) (0.64 mol dm(-3) h(-1)). The most electron rich complex, [Rh(Cp'(CH(2))(2)PEt(2))(CO)] (0.38 mol dm(-3) h(-1)) gave a comparable rate to [Cp*Rh(PEt(3))(CO)] (0.30 mol dm(-3) h(-1)), which was unstable towards oxidation of the phosphine. [Rh(Cp'(CH(2))(2)PEt(2))I(2)], which is inactive for methanol carbonylation, was isolated after the methanol carbonylation reaction using [Rh(Cp'(CH(2))(2)PEt(2))(CO)]. Neither of [M(Cp'(CH(2))(2)PEt(2))(CO)] (M = Co or Ir) was active for methanol carbonylation under these conditions, nor under many other conditions investigated, except that [Ir(Cp'(CH(2))(2)PEt(2))(CO)] showed some activity at higher temperature (190 degrees C), probably as a result of degradation to [IrI(2)(CO)(2)](-). [M(Cp'(CH(2))(2)PEt(2))(CO)] react with MeI to give [M(Cp'(CH(2))(2)PEt(2))(C(O)Me)I] (M = Co or Rh) or [Ir(Cp'(CH(2))(2)PEt(2))Me(CO)]I. The rates of oxidative addition of MeI to [Rh(C(5)H(4)(CH(2))(2)PEt(2))(CO)] and [Rh(Cp'(CH(2))(2)PPh(2))(CO)] are 62 and 1770 times faster than to [Cp*Rh(CO)(2)]. Methyl migration is slower, however. High pressure NMR studies show that [Co(Cp'(CH(2))(2)PEt(2))(CO)] and [Cp*Rh(PEt(3))(CO)] are unstable towards phosphine oxidation and/or quaternisation under methanol carbonylation conditions, but that [Rh(Cp'(CH(2))(2)PEt(2))(CO)] does not exhibit phosphine degradation, eventually producing inactive [Rh(Cp'(CH(2))(2)PEt(2))I(2)] at least under conditions of poor gas mixing. The observation of [Rh(Cp'(CH(2))(2)PEt(2))(C(O)Me)I] under methanol carbonylation conditions suggests that the rhodium centre has become so electron rich that reductive elimination of ethanoyl iodide has become rate determining for methanol carbonylation. In addition to the high electron density at rhodium.


The risk factors and prognosis of bilateral primary breast cancer: a comparative study with unilateral breast cancer.
This study was performed to determine the risk factors and evaluate the outcome of bilateral breast cancer (BBC). We reviewed the records of 170 patients with BBC and 1,677 with unilateral breast cancer (UBC), and compared their personal history, histopatholgical characteristics, clinical findings, and treatment, and postoperative follow-up records. The patients with UBC were more likely to develop contralateral cancer with the features including: young age at onset, especially younger than 40, premenopause, late primiparity, breast cancer family history, benign mammary disease history, and a tumor larger than 5 cm (p < 0.05). After adjustment by multivariate analysis, we concluded that breast cancer family history and age at onset younger than 40 years old were the independent risk factors for BBC. There were no significant differences for distant metastasis or overall survival between BBC and UBC (p > 0.05). We observed that 64.1% of the second breast cancer occurred within 5 years after the operation of the first cancer, and medical examination could improve the early diagnosis of the contralateral breast cancer. Contrary to common belief, our study showed that BBC and UBC had similar biological features and prognosis (p > 0.05). The excessive treatment and prophylactic measures may be unnecessary in this seemingly aggressive breast cancer. The patients with UBC younger than 40 or with breast cancer family history should have intensive contralateral breast followup, especially within 5 years after in the initial treatment.


Stress-induced changes in group behaviour.
Testing animals in groups can provide valuable data for investigating behavioural stress responses. However, conventional measures typically focus on the behaviour of individual animals or on dyadic interactions. Here, we aimed to determine metrics describing the behaviour of grouping animals that can reveal differences in stress responses. Using zebrafish (Danio rerio) as a model, we observed replicated shoals both immediately and 24 hours after exposure to a novel environment, as an assessment of temporal change in response to an acute stressor. We quantified various standard behavioural measures in combination with metrics describing group structure, including different proximity, social, and spatial metrics. Firstly, we showed a high collinearity between most of the analysed metrics, suggesting that they describe similar aspects of the group dynamics. After metric selection, we found that under acute stress shoals had significantly higher shoal densities, a lower variation in nearest neighbour distances and were in closer proximity to the walls compared to the same groups tested 24 hours later, indicating a reduction in acute stress over time. Thus, the use of group metrics could allow for the refinement of behavioural protocols carried out in a range of research areas, by providing sensitive and rich data in a more relevant social context.


The MAPS Reporting Statement for Studies Mapping onto Generic Preference-Based Outcome Measures: Explanation and Elaboration.
The process of "mapping" is increasingly being used to predict health utilities, for application within health economic evaluations, using data on other indicators or measures of health. Guidance for the reporting of mapping studies is currently lacking. The overall objective of this research was to develop a checklist of essential items, which authors should consider when reporting mapping studies. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a checklist, which aims to promote complete and transparent reporting by researchers. This paper provides a detailed explanation and elaboration of the items contained within the MAPS statement. In the absence of previously published reporting checklists or reporting guidance documents, a de novo list of reporting items and accompanying explanations was created. A two-round, modified Delphi survey, with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community, was used to identify a list of essential reporting items from this larger list. From the initial de novo list of 29 candidate items, a set of 23 essential reporting items was developed. The items are presented numerically and categorised within six sections, namely, (i) title and abstract, (ii) introduction, (iii) methods, (iv) results, (v) discussion and (vi) other. For each item, we summarise the recommendation, illustrate it using an exemplar of good reporting practice identified from the published literature, and provide a detailed explanation to accompany the recommendation. It is anticipated that the MAPS statement will promote clarity, transparency and completeness of reporting of mapping studies. It is targeted at researchers developing mapping algorithms, peer reviewers and editors involved in the manuscript review process for mapping studies, and the funders of the research. The MAPS working group plans to assess the need for an update of the reporting checklist in 5 years' time.


High prevalence of hantavirus antibodies in bank voles (Clethrionomys glareolus) captured in the vicinity of households afflicted with nephropathia epidemica.
Puumala virus, the causative agent of nephropathia epidemica (NE), occurs endemically in Europe and is spread mainly by the bank vole (Clethrionomys glareolus). In the vicinity of each of four households afflicted with NE, we studied rodents with regard to population density and prevalence of Puumala virus-specific antibodies. For each case area, a control area was randomly selected 10 km away, without regard to the presence of human settlement. During 6,000 trap nights, 328 rodents were caught, of which 299 were C. glareolus. The mean rodent densities of case and control areas were 6.6 and 3.7 animals per 100 trap nights (P < 0.001). The prevalence of serum antibodies was 15.9% in case areas compared with 5.6% in control areas (P < 0.05). In three of the case areas, where NE had occurred 3-10 weeks before trapping, the rodent density and seroprevalence were much higher than in the fourth area, where NE occurred 38 weeks before trapping. In conclusion, C. glareolus seropositive for Puumala virus occurred more frequently near households afflicted with NE than in control areas 10 km away.


Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes.
Pre-eclampsia (PE) affects 5-7% of pregnancies in the US, and is a leading cause of maternal death and perinatal morbidity and mortality worldwide. To identify genes with a role in PE, we conducted a large-scale association study evaluating 775 SNPs in 190 candidate genes selected for a potential role in obstetrical complications. SNP discovery was performed by DNA sequencing, and genotyping was carried out in a high-throughput facility using the MassARRAY(TM) System. Women with PE (n = 394) and their offspring (n = 324) were compared with control women (n = 602) and their offspring (n = 631) from the same hospital-based population. Haplotypes were estimated for each gene using the EM algorithm, and empirical p values were obtained for a logistic regression-based score test, adjusted for significant covariates. An interaction model between maternal and offspring genotypes was also evaluated. The most significant findings for association with PE were COL1A1 (p = 0.0011) and IL1A (p = 0.0014) for the maternal genotype, and PLAUR (p = 0.0008) for the offspring genotype. Common candidate genes for PE, including MTHFR and NOS3, were not significantly associated with PE. For the interaction model, SNPs within IGF1 (p = 0.0035) and IL4R (p = 0.0036) gave the most significant results. This study is one of the most comprehensive genetic association studies of PE to date, including an evaluation of offspring genotypes that have rarely been considered in previous studies. Although we did not identify statistically significant evidence of association for any of the candidate loci evaluated here after adjusting for multiple testing using the false discovery rate, additional compelling evidence exists, including multiple SNPs with nominally significant p values in COL1A1 and the IL1A region, and previous reports of association for IL1A, to support continued interest in these genes as candidates for PE. Identification of the genetic regulators of PE may have broader implications, since women with PE are at increased risk of death from cardiovascular diseases later in life.


Population Exposure to Phthalate-containing Drugs.
Phthalates are known endocrine disruptors. Not commonly recognized, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate-containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from medstat.dk. Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the 'defined daily dose' (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethyl phthalate (DEP) and dibutyl phthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate-containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low-molecular-weight phthalates and three high-molecular-weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multi-enzymes (24.6-32.8 mg per DDD) and mesalazine (12.5-26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate-containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.


Homer as both a scaffold and transduction molecule.
Increasing evidence shows that scaffold proteins not only control membrane assembly of receptors and channels, but also modulate intracellular signaling by assembled receptors. The Homer family of proteins act as scaffolds to bind clusters of proteins and glutamate receptors at postsynaptic sites. We review results of cloning and gene expression of this protein family, and summarize roles in glutamate receptor function and intracellular signaling in neurons. Homer proteins trigger the localization of metabotropic glutamate receptor subtype 5 (mGlu5 receptor) to the postsynaptic plasma membrane. They can also alter the kinetics and peak amplitude of the intracellular Ca2+ responses of mGlu1 and mGlu5 receptors. Homer proteins can either prevent or promote spontaneous activation of these receptors, depending on the type of Homer protein isoform expressed.


Hormonal control of p53 and chemoprevention.
Improvements in the detection and treatment of breast cancer have dramatically altered its clinical course and outcome. However, prevention of breast cancer remains an elusive goal. Parity, age of menarche, and age at menopause are major risk factors drawing attention to the important role of the endocrine system in determining the risk of breast cancer, while heritable breast cancer susceptibility syndromes have implicated tumor suppressor genes as important targets. Recent work demonstrating hormonal modulation of the p53 tumor suppressor pathway draws together these established determinants of risk to provide a model of developmental susceptibility to breast cancer. In this model, the mammary epithelium is rendered susceptible due to impaired p53 activity during specific periods of mammary gland development, but specific endocrine stimuli serve to activate p53 function and to mitigate this risk. The results focus attention on p53 as a molecular target for therapies to reduce the risk of breast cancer.


Evaluation of immunisation coverage for aboriginal and Torres Strait Islander children using the Australian Childhood Immunisation Register.
To estimate immunisation coverage for routinely administered vaccines among children using receipt of a particular Hib vaccine (PRP-OMP) as a proxy for Indigenous status. Until May 2000, PRP-OMP was provided only for Indigenous children in all jurisdictions except the Northern Territory. In three one-year ACIR-derived birth cohorts, any child recorded on the ACIR as receiving one or more doses of PRP-OMP as the only Hib vaccine was presumed to be Aboriginal and Torres Strait Islander. Using this proxy, estimated numbers of Indigenous children were compared with Australian Bureau of Statistics estimates, and immunisation status for recommended vaccines was estimated at 12 and 24 months by jurisdiction and remoteness compared with children who received other Hib vaccines (presumed non-Indigenous). The numbers of Aboriginal and Torres Strait Islander children estimated using this 'proxy method' are approximately 42% of those estimated by the ABS. Immunisation coverage (among proxy Indigenous children) at 12 months (72-76%) and 24 months (64-73%) was considerably lower than others (90-94% and 81-88%, respectively). These children had significantly lower coverage when living in accessible areas than remote areas. These data provide the first national measure of immunisation status and are likely to be a valid measure among those identified. Aboriginal and Torres Strait Islander immunisation coverage is 17% lower with the biggest gaps in urban areas, indicating the need for better quality data informing appropriate interventions.


New insights into the impact of Lactobacillus population on host-bacteria metabolic interplay.
We aimed at evaluating the association between intestinal Lactobacillus sp. composition and their metabolic activity with the host metabolism in adult and elderly individuals. Faecal and plasma metabolites were measured and correlated to the Lactobacillus species distribution in healthy Estonian cohorts of adult (n = 16; < 48 y) and elderly (n = 33; > 65 y). Total cholesterol, LDL, C-reactive protein and glycated hemoglobin were statistically higher in elderly, while platelets, white blood cells and urinary creatinine were higher in adults. Aging was associated with the presence of L. paracasei and L. plantarum and the absence of L. salivarius and L. helveticus. High levels of intestinal Lactobacillus sp. were positively associated with increased concentrations of faecal short chain fatty acids, lactate and essential amino acids. In adults, high red blood cell distribution width was positively associated with presence of L. helveticus and absence of L. ruminis. L. helveticus was correlated to lactate and butyrate in faecal waters. This indicates a strong relationship between the composition of the gut Lactobacillus sp. and host metabolism. Our results confirm that aging is associated with modulations of blood biomarkers and intestinal Lactobacillus species composition. We identified specific Lactobacillus contributions to gut metabolic environment and related those to blood biomarkers. Such associations may prove useful to decipher the biological mechanisms underlying host-gut microbial metabolic interactions in an ageing population.


Using a novel exercise programme for patients with muscular dystrophy. Part I: a qualitative study.
Muscular dystrophy patients have often experimented with different alternative or complementary methods since there is at present no curative medical treatment. To evaluate, through qualitative analysis of interview data, the subjective experiences of twenty-eight patients with muscular dystrophy practising a complementary method, qigong. Semi-structured qualitative interviews were performed and data were analysed by a method inspired by Grounded Theory. The material was first coded into 119 categories, thereafter condensed to 59 categories through a constant comparison analysis. In the final analysis, six broad categories were formed out of these 59 categories. These broad categories were: (1) experience of health care and alternative methods; (2) expectations, acceptance and compliance; (3) qigong as an adaptable form of exercise; (4) stress reduction and mental effects; (5) increased body awareness and physical effects; (6) psychosocial effects of group training. Qigong was accepted as a novel exercise regimen and there was a wide variation of experience regarding it among the participants. Depending upon factors such as expectation of benefits, time available to do qigong and perceived effects doing it, compliance varied. One major advantage of qigong is the ability to adapt the different exercises to the physical capability of the person practising qigong. There were reports of mental, physical and psychosocial effects of the qigong, which reduced the feeling of stress and improved well-being.


Differential infection properties of three inducible prophages from an epidemic strain of Pseudomonas aeruginosa.
Pseudomonas aeruginosa is the most common bacterial pathogen infecting the lungs of patients with cystic fibrosis (CF). The Liverpool Epidemic Strain (LES) is transmissible, capable of superseding other P. aeruginosa populations and is associated with increased morbidity. Previously, multiple inducible prophages have been found to coexist in the LES chromosome and to constitute a major component of the accessory genome not found in other sequenced P. aerugionosa strains. LES phages confer a competitive advantage in a rat model of chronic lung infection and may, therefore underpin LES prevalence. Here the infective properties of three LES phages were characterised. This study focuses on three of the five active prophages (LESφ2, LESφ3 and LESφ4) that are members of the Siphoviridae. All were induced from LESB58 by norfloxacin. Lytic production of LESφ2 was considerably higher than that of LESφ3 and LESφ4. Each phage was capable of both lytic and lysogenic infection of the susceptible P. aeruginosa host, PAO1, producing phage-specific plaque morphologies. In the PAO1 host background, the LESφ2 prophage conferred immunity against LESφ3 infection and reduced susceptibility to LESφ4 infection. Each prophage was less stable in the PAO1 chromosome with substantially higher rates of spontaneous phage production than when residing in the native LESB58 host. We show that LES phages are capable of horizontal gene transfer by infecting P. aeruginosa strains from different sources and that type IV pili are required for infection by all three phages. Multiple inducible prophages with diverse infection properties have been maintained in the LES genome. Our data suggest that LESφ2 is more sensitive to induction into the lytic cycle or has a more efficient replicative cycle than the other LES phages.


Can a random serum cortisol reduce the need for short synacthen tests in acute medical admissions?
Short synacthen tests (SSTs) are frequently performed in medical inpatients with suspected adrenocortical insufficiency. The utility of a random or baseline serum cortisol in this setting is unclear. We determined random cortisol thresholds that safely preclude SSTs in acute medical admissions. We analysed SSTs in acute non-critically ill general medical patients (n = 166, median age 66, range 15-94 y; men 48%, women 52%). The SST was defined according to the 30-min cortisol as 'pass' (>550 nmol/L) or 'fail' (< or =550 nmol/L). Receiver operating characteristics (ROC) curves were generated to determine the predictive value of the basal cortisol for a failed SST. Of 166 SSTs, a pass was seen in 127 (76.5%) tests, while 39 (23.5%) tests failed the SST. ROC curves showed that no single cut-off point of the baseline cortisol was adequately both sensitive and specific for failing the SST despite a good overall predictive value (area under curve 0.94; 95% confidence interval 0.89-0.98). A basal cortisol <420 nmol/L had 100% sensitivity and 54% specificity for failing the SST, while a basal cortisol <142 nmol/L had 100% specificity and 35% sensitivity. Restricting the SST to patients with a basal cortisol <420 nmol/L would have prevented 44% of SSTs while correctly identifying all patients who failed the SST. A baseline serum cortisol may prevent unnecessary SSTs in medical inpatients with suspected adrenocortical insufficiency. However, SSTs are still indicated in patients with random cortisol <420 nmol/L, or where the suspicion of adrenal insufficiency is compelling.


Fluoro-substituted cyanine for reliable in vivo labelling of amyloid-β oligomers and neuroprotection against amyloid-β induced toxicity.
Alzheimer's disease (AD) is the most prevalent but still incurable neurodegenerative form of dementia. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. We herein report a novel fluoro-substituted cyanine, F-SLOH, which exhibits good Aβ oligomer selectivity with a high binding affinity, attributed to the synergistic effect of strong π-π stacking and intermolecular CH···O and CH···F interactions. The selectivity towards the Aβ oligomers in the brain was ascertained by in vitro labelling on tissue sections and in vivo labelling through the systemic administration of F-SLOH in 7 month APP/PS1 double transgenic (Tg) and APP/PS1/Tau triple Tg mouse models. F-SLOH also shows remarkably effective inhibition on Aβ aggregation and highly desirable neuroprotective effects against Aβ-induced toxicities, including the inhibition of ROS production and Ca2+ influx. Its excellent blood-brain barrier (BBB) penetrability and low bio-toxicity further support its tremendous potential as a novel theranostic agent for both early diagnosis and therapy of AD.


Observations of nitrogen isotope fractionation in deeply embedded protostars.
The terrestrial planets, comets, and meteorites are significantly enriched in 15N compared to the Sun and Jupiter. While the solar and jovian nitrogen isotope ratio is believed to represent the composition of the protosolar nebula, a still unidentified process has caused 15N-enrichment in the solids. Several mechanisms have been proposed to explain the variations, including chemical fractionation. However, observational results that constrain the fractionation models are scarce. While there is evidence of 15N-enrichment in prestellar cores, it is unclear how the signature evolves into the protostellar phases. The aim of this study is to measure the 14N/15N ratio around three nearby, embedded low- to intermediate-mass protostars. Isotopologues of HCN and HNC were used to probe the 14N/15N ratio. A selection of J = 3-2 and 4-3 transitions of H13CN, HC15N, HN13C, and H15NC was observed with the Atacama Pathfinder EXperiment telescope (APEX). The 14N/15N ratios were derived from the integrated intensities assuming a standard 12C/13C ratio. The assumption of optically thin emission was verified using radiative transfer modeling and hyperfine structure fitting. Two sources, IRAS 16293A and R CrA IRS7B, show 15N-enrichment by a factor of ~1.5-2.5 in both HCN and HNC with respect to the solar composition. IRAS 16293A falls in the range of typical prestellar core values. Solar composition cannot be excluded for the third source, OMC-3 MMS6. Furthermore, there are indications of a trend toward increasing 14N/15N ratios with increasing outer envelope temperature. The enhanced 15N abundances in HCN and HNC found in two Class 0 sources (14N/15N ~ 160-290) and the tentative trend toward a temperature-dependent 14N/15N ratio are consistent with the chemical fractionation scenario, but 14N/15N ratios from additional tracers are indispensable for testing the models. Spatially resolved observations are needed to distinguish between chemical fractionation and isotope-selective photochemistry.


Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies.
Tadalafil has regulatory approval for the treatment of men with signs/symptoms of benign prostatic hyperplasia with and without erectile dysfunction. We assessed whether the effects of treatment with tadalafil for lower urinary tract symptoms/benign prostatic hyperplasia are independent of improvements in erectile dysfunction. Four separate analyses used integrated data from 4 randomized, double-blind, placebo controlled studies in men with lower urinary tract symptoms/benign prostatic hyperplasia with and without erectile dysfunction to test whether total I-PSS (International Prostate Symptom Score) improvement was due to improvement in IIEF-EF (International Index of Erectile Function-Erectile Function domain score). Unidirectional and bidirectional path analysis models determined direct and indirect treatment effects mediated by improvements in lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction symptoms. A total of 1,496 men, of whom 77% had erectile dysfunction, received at least 1 dose of tadalafil 5 mg once daily or placebo. The placebo adjusted treatment effect for men with erectile dysfunction was represented by a mean decrease of -2.3 (p <0.0001) in total I-PSS vs -2.2 (p = 0.0007) for men without erectile dysfunction. The correlation between change from baseline in total I-PSS and IIEF-EF was weak (r(2) = 0.08, p <0.0001). The unidirectional path analysis model suggested that the total treatment effect on total I-PSS score improvement (2.25) was derived from a direct treatment effect of 1.57 (70%, p <0.001) and an indirect treatment effect of 0.67 (30% via IIEF-EF improvement, p <0.001). Bidirectional path analysis showed that total I-PSS improvement was largely attributed to direct (92.5%, p <0.001) vs indirect (7.5%, p = 0.32) treatment effects via IIEF-EF improvement. Regardless of the analytical approach, self-reported erectile dysfunction status did not appreciably influence tadalafil treatment response in men with lower urinary tract symptoms/benign prostatic hyperplasia, supporting the dual action of tadalafil on lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction.


Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function.
Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.


A virus-encoded "superantigen" in a retrovirus-induced immunodeficiency syndrome of mice.
The development of an immunodeficiency syndrome of mice caused by a replication-defective murine leukemia virus (MuLV) is paradoxically associated with a rapid activation and proliferation of CD4+ T cells that are dependent on the presence of B cells. The responses of normal spleen cells to B cell lines that express the defective virus indicated that these lines express a cell surface determinant that shares "superantigenic" properties with some microbial antigens and Mls-like self antigens. This antigen elicited a potent proliferative response that was dependent on the presence of CD4+ T cells and was associated with selective expansion of cells bearing V beta 5. This response was markedly inhibited by a monoclonal antibody specific for the MuLV gag-encoded p30 antigen.


Nutritional Practices and Growth in Premature Infants After Surgical Necrotizing Enterocolitis.
The aim of the study was to describe the nutritional provisions received by infants with surgical necrotizing enterocolitis (NEC) and the associated effects on short-term growth. Through the Children's Hospitals Neonatal Database, we identified infants born ≤32 weeks' gestation with surgical NEC from 5 regional neonatal intensive care units for 4 years. Excluded infants had isolated intestinal perforation and died <14 days postoperatively. Infants were stratified by their median parenteral protein dose (low [LP] or high [HP] protein) for the first postoperative week. The primary outcome was postoperative weight growth velocity. Growth (weight, length, and head circumference [HC]) was measured and the effects related to protein dose were estimated using multivariable analyses. There were 103 infants included; the median parenteral protein dose received was 3.27 g · kg · day (LP: 2.80 g · kg · day; HP: 3.87 g · kg · day). Postoperative weight (11.5 ± 6.5 g · kg · day) and linear growth (0.9 ± 0.2 cm/wk) were similar regardless of dose (P > 0.3 between groups for weight and length). Unadjusted and independent associations were identified with HC changes and HP dose (β = 0.1 cm/wk, P = 0.03) after adjusting for gestational age, the presence of severe bronchopulmonary dysplasia, short bowel syndrome, blood stream infection, severe intraventricular hemorrhage, small for gestational age, and calorie intake. Eventual nonsurvivors received 18% less protein and 14% fewer calories over the first postoperative month. Postoperative protein doses in infants with surgical NEC appear related to increases in HC. The influence of postoperative nutritional support on risk of adverse outcomes deserves further attention.


Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial.
Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77-1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66-1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14-4·29); for patients who were antibody negative, the OR was 0·51 (0·29-0·90; pinteraction=0·001). When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. US National Institutes of Health.


Delivery of angiotensin II type 1 receptor antisense inhibits angiotensin action in neurons from hypertensive rat brain.
Increased brain angiotensin II (AII) type 1 receptor (AT1R) expression has been implicated in the hyperactive brain angiotensin system and the development and maintenance of hypertension in the genetically spontaneously hypertensive (SH) rat. Neuronal cells in primary culture from the cardioregulatory-relevant brain areas (hypothalamus/brainstem) mimic increased brain AT1R gene expression and AT1R function of the adult SH rat. They have been utilized in the present study to determine whether cellular actions of AII could be regulated by the transfer of AT1R antisense (AT1R-AS) with the use of a retroviral-mediated gene delivery system developed for the central nervous system cultures. AII stimulates norepinephrine (NE) uptake in neuronal cultures of both normotensive (Wistar Kyoto) and SH rat brains. This neuromodulatory action is mediated by the AT1R subtype, is significantly higher in SH neurons, and is associated with a parallel stimulation of mRNAs for c-fos and NE transporter. Infection of neuronal cultures with a retrovirus vector that contains AT1R-AS (LNSV-AT1R-AS) results in an inhibition of AT1R-mediated stimulation of both c-fos and NE transporter mRNA, as well as NE uptake in both strains of rats; however, the inhibition is more pronounced in SH neurons compared with Wistar Kyoto rat brain neurons. The higher sensitivity of the SH rat brain neurons is further supported by our observation that a certain dose of LNSV-AT1R-AS that fails to induce inhibition of cellular actions of AII in WKY neurons causes a significant inhibition of AII actions in SH neurons. These observations show that retrovirally mediated delivery of AT1R-AS could be used to selectively control the actions of AII in primary neuronal cultures from SH rat brain.


Analysis of sequence and structural features that identify the B/C motif of U3 small nucleolar RNA as the recognition site for the Snu13p-Rrp9p protein pair.
The eukaryal Snu13p/15.5K protein binds K-turn motifs in U4 snRNA and snoRNAs. Two Snu13p/15.5K molecules bind the nucleolar U3 snoRNA required for the early steps of preribosomal processing. Binding of one molecule on the C'/D motif allows association of proteins Nop1p, Nop56p, and Nop58p, whereas binding of the second molecule on the B/C motif allows Rrp9p recruitment. To understand how the Snu13p-Rrp9p pair recognizes the B/C motif, we first improved the identification of RNA determinants required for Snu13p binding by experiments using the systematic evolution of ligands by exponential enrichment. This demonstrated the importance of a U.U pair stacked on the sheared pairs and revealed a direct link between Snu13p affinity and the stability of helices I and II. Sequence and structure requirements for efficient association of Rrp9p on the B/C motif were studied in yeast cells by expression of variant U3 snoRNAs and immunoselection assays. A G-C pair in stem II, a G residue at position 1 in the bulge, and a short stem I were found to be required. The data identify the in vivo function of most of the conserved residues of the U3 snoRNA B/C motif. They bring important information to understand how different K-turn motifs can recruit different sets of proteins after Snu13p association.


Functional p53 is required for rapid restoration of daunorubicin-induced lesions of the spleen.
The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen. Mice with wild type or deleted Trp53 were treated with the daunorubicin (DNR) for three consecutive days. Spleens were collected at various time points after treatment, and examined for signs of chemotherapy-related lesions by microscopic analysis of haematoxylin-eosin or tunel-stained paraffin sections. Expression of death-inducing proteins was analysed by immunoblotting. Changes between Trp53 wild type and null mice were compared by t-tests. Signs of cell death (pyknotic nuclei and tunel-positive cells) in the white pulp of the spleen occurred earlier following DNR exposure in wt-mice compared to Trp53-null mice. While the spleen of wt-mice recovered to normal morphology, the spleen of the Trp53-null animals still had lesions with large necrotic areas and disorganised histologic appearance eight days after treatment. Immunoblotting showed that only Trp53-wt mice had significant increase in p21 after DNR treatment. However, both wt and null mice had elevated p63 levels following DNR exposure. p53 protects against severe and enduring cellular damage of the spleen parenchyma after DNR treatment, and initial DNR-induced apoptosis is not predictive of tissue lesions in the spleen. Our data indicate that p53 induction following DNR treatment serves to protect rather than to destroy normal tissue.


Evaluating hemispheric divisions in processing fixated words: the evidence from Arabic.
Some studies have claimed that, when fixating a word, a precise split in foveal processing produces substantial effects on word recognition because all letters to the left and right of fixation project to different, contralateral hemispheres. Recently in this Journal, Jordan, Paterson, Kurtev, and Xu (2010, Cortex, 46, 298-309) evaluated this claim using precisely-controlled procedures of fixation and stimulus presentation and found no evidence of split-foveal processing. However, in line with other research in this area, these findings were obtained using a Latinate alphabetic language (in this case English) which may induce specific effects on performance. Consequently, here we report a further study which used stimuli from a fundamentally different, non-Latinate alphabetic language (Arabic) with characteristics better suited to revealing effects of split-foveal processing, if they exist. Participants made lexical decisions to five-letter Arabic words (and nonwords) when fixations were made immediately to the right (location 1) or left (location 6) of each stimulus, or at one of the four possible inter-letter locations (locations 2-5). Fixation location was carefully controlled using an eye-tracker linked to a fixation-contingent display and all stimuli were presented within foveal vision to avoid confounding influences of extrafoveal projections. Performance was equally poorest when fixating locations 1 and 6 (i.e., when words were shown entirely to either the left or right of fixation), equally intermediate for locations 2 and 5, and equally superior for locations 3 and 4 (i.e., the centre of words). Moreover, additional, word-specific analyses showed no evidence of the effects of fixation location on individual word recognition also predicted by split-foveal processing. These findings from a non-Latinate language complement those reported previously for English to provide further evidence that while fixation location influences word recognition, these influences occur with no functional division in hemispheric processing at the point of fixation.


Practical and Ethical Concerns in Implementing Enhanced Surveillance Methods to Improve Continuity of HIV Care: Qualitative Expert Stakeholder Study.
Retention in HIV care is critical to maintaining viral suppression and preventing further transmission, yet less than 50% of people living with HIV in the United States are engaged in care. All US states have a funding mandate to implement Data-to-Care (D2C) programs, which use surveillance data (eg, laboratory, Medicaid billing) to identify out-of-care HIV-positive persons and relink them to treatment. The purpose of this qualitative study was to identify and describe practical and ethical considerations that arise in planning for and implementing D2C. Via purposive sampling, we recruited 43 expert stakeholders-including ethicists, privacy experts, researchers, public health personnel, HIV medical providers, legal experts, and community advocates-to participate in audio-recorded semistructured interviews to share their perspectives on D2C. Interview transcripts were analyzed across a priori and inductively derived thematic categories. Stakeholders reported practical and ethical concerns in seven key domains: permission and consent, government assistance versus overreach, privacy and confidentiality, stigma, HIV exceptionalism, criminalization, and data integrity and sharing. Participants expressed a great deal of support for D2C, yet also stressed the role of public trust and transparency in addressing the practical and ethical concerns they identified.


It's the nature of the work: examining behavior-based sources of work-family conflict across occupations.
The consequences of work-family conflict for both individuals and organizations have been well documented, and the various sources of such conflict have received substantial attention. However, the vast majority of extant research has focused on only time- and strain-based sources, largely neglecting behavior-based sources. Integrating two nationally representative databases, the authors examine 3 behavior-based antecedents of work-family conflict linked specifically to occupational work role requirements (interdependence, responsibility for others, and interpersonal conflict). Results from multilevel analysis indicate that significant variance in work-family conflict is attributable to the occupation in which someone works. Interdependence and responsibility for others predict work-family conflict, even after controlling for several time- and strain-based sources.


Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions - United States, March-August 2021.
Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p<0.001). Protection for the Pfizer-BioNTech vaccine declined 4 months after vaccination. Postvaccination anti-spike IgG and anti-RBD IgG levels were significantly lower in persons vaccinated with the Janssen vaccine than the Moderna or Pfizer-BioNTech vaccines. Although these real-world data suggest some variation in levels of protection by vaccine, all FDA-approved or authorized COVID-19 vaccines provide substantial protection against COVID-19 hospitalization.


Twelve novel mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL) in patients with various forms of hypophosphatasia.
Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report here the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 11 families affected by various forms of hypophosphatasia. Nineteen distinct mutations were found, 7 of which were previously reported. Eleven of the 12 new mutations were missense mutations (Y11C, A34V, R54H, R135H, N194D, G203V, E218G, D277Y, F310G, A382S, V406A), the last one (998-1G>T) was a mutation affecting acceptor splice site.


Validity of the Center for Epidemiological Studies Depression Scale in arthritis populations.
Using data from 3 studies of patients with rheumatoid arthritis, we examined the extent to which responses to items in the Center for Epidemiological Studies Depression Scale (CES-D) are influenced by aspects of the disease process other than depression. Our findings suggested that 4 CES-D items (i.e., "I felt that everything I did was an effort," "I felt hopeful about the future," "My sleep was restless," and "I could not get going") may be influenced by aspects of the disease process and, thus, are not necessarily indicative of depression among persons with arthritis. The impact that these items have on the interpretation of CES-D scores was assessed in relation to 2 research issues: estimation of the prevalence and severity of depression in arthritis populations and identification of the determinants of depression among individuals with arthritis. Our results suggest that the original CES-D may overestimate the prevalence and severity of depression among patients with arthritis. The magnitude of this bias is modest, however. The results also suggest that in studies designed to identify the determinants of depression among individuals with arthritis, inclusion of the 4 items identified is unlikely to have any effect on study findings.


Memory maintenance via neuronal regulation.
Since their conception half a century ago, Hebbian cell assemblies have become a basic term in the neurosciences, and the idea that learning takes place through synaptic modifications has been accepted as a fundamental paradigm. As synapses undergo continuous metabolic turnover, adopting the stance that memories are engraved in the synaptic matrix raises a fundamental problem: How can memories be maintained for very long time periods? We present a novel solution to this long-standing question, based on biological evidence of neuronal regulation mechanisms that act to maintain neuronal activity. Our mechanism is developed within the framework of a neural model of associative memory. It is operative in conjunction with random activation of the memory system and is able to counterbalance degradation of synaptic weights and normalize the basins of attraction of all memories. Over long time periods, when the variance of the degradation process becomes important, the memory system stabilizes if its synapses are appropriately bounded. Thus, the remnant memory system is obtained by a dynamic process of synaptic selection and growth driven by neuronal regulatory mechanisms. Our model is a specific realization of dynamic stabilization of neural circuitry, which is often assumed to take place during sleep.


Clinical, pathological and radiological evaluation of disseminated Langerhans' cell histiocytosis in a 30-month-old boy.
Langerhans' cell histiocytosis is a rare disease characterized histologically by the proliferation of Langerhans' cells. Oral involvement is frequent and the disease simulates severe localized periodontitis. In this report, we present a case of disseminated Langerhans' cell histiocytosis in a 30-month-old boy who had a mass covering the entire maxillopalatine region and suffered severe periodontal destruction in the posterior maxilla and mandible. We discuss the radiological, histopathological and immunohistochemical findings.


Membrane treatment of the bleaching plant (EPO) filtrate of a kraft pulp mill.
The objective of this study was to evaluate the use of membrane technology to treat oxygen and peroxide-reinforced extraction stage (EPO) filtrate from a kraft pulp mill bleach plant. Three different types of tubular membranes were tested in a pilot plant: (i) tight ultrafiltration (UF); (ii) open UF followed by nanofiltration (UF+NF); and (iii) nanofiltration (NF). According to the separation performance, considering the chemical oxygen demand (COD) and colour removal, permeate flux, operational simplicity and cost, the results indicated that the best option for treatment of (EPO) filtrates was the tight UF membrane. This membrane obtained a COD removal of 79% with a colour reduction of 86%. The effect of (EPO) filtrate UF treatment on the mill effluent treatment plant was evaluated. Compared with the actual mill effluent, the results indicated that if the UF permeate was recycled in the bleaching area, the COD reduction efficiency increased by 7%, the final effluent colour decreased by 8%, the biological sludge production decreased by 18%, and the energy consumption decreased by 40%. In the tertiary treatment plant, the coagulant dosage decreased by 40%, and the tertiary sludge production decreased by 46%.


Missing documentation of weight and height at preventive visits for children.
Despite the importance of measuring weight and height at well-child visits, there are limited data on frequency of anthropometric documentation. The authors aimed to identify characteristics associated with missing weight and height documentation at preventive visits for children. Among preventive visits for children from birth to 18 years old, recorded in the National Ambulatory Medical Care and National Hospital Ambulatory Medical Care Surveys for 2005-2009, the authors found that 20.8% had missing weight and/or height (n = 19,033) documentation. Compared with infants younger than 2 years, school-age children (odds ratio [OR] = 1.30; 95% confidence interval [CI] = 1.03-1.64), and adolescents (OR = 1.61; 95% CI = 1.26-2.04) were more likely to lack documentation. Missing documentation was also more likely for visits with nonphysicians (OR = 4.53; 95% CI = 3.17-6.48) and nonpediatricians (OR = 2.63; 95% CI = 2.02-3.41) compared with pediatricians. Efforts to improve weight and height surveillance should be directed to clinics in which midlevel providers and nonpediatric physicians are caring for school-age children and adolescents.


Optimization of fluorogenic RNA-based biosensors using droplet-based microfluidic ultrahigh-throughput screening.
Biosensors are biological molecules able to detect and report the presence of a target molecule by the emission of a signal. Nucleic acids are particularly appealing for the design of such molecule since their great structural plasticity makes them able to specifically interact with a wide range of ligands and their structure can rearrange upon recognition to trigger a reporting event. A biosensor is typically made of three main domains: a sensing domain that is connected to a reporting domain via a communication module in charge of transmitting the sensing event through the molecule. The communication module is therefore an instrumental element of the sensor. This module is usually empirically developed through a trial-and-error strategy with the testing of only a few combinations judged relevant by the experimenter. In this work, we introduce a novel method combining the use of droplet-based microfluidics and next generation sequencing. This method allows to functionally characterize up to a million of different sequences in a single set of experiments and, by doing so, to exhaustively test every possible sequence permutations of the communication module. Here, we demonstrate the efficiency of the approach by isolating a set of optimized RNA biosensors able to sense theophylline and to convert this recognition into fluorescence emission.


Measuring mindfulness: pilot studies with the Swedish versions of the Mindful Attention Awareness Scale and the Kentucky Inventory of Mindfulness Skills.
The present article describes data from pilot studies with the Swedish versions of the Mindful Attention Awareness Scale (MAAS) and the Kentucky Inventory of Mindfulness Skills (KIMS). The MAAS and two of the KIMS scales, Act with Awareness and Accept without Judgment, were found to correlate in the predicted direction with measures of well-being and emotional distress. The KIMS scales Observe and Describe showed more ambiguous results, possibly because these two scales measure a mixture of two opposite kinds of processes: healthy self-observation ("experiential self-focus") and unhealthy rumination ("analytical self-focus"). The KIMS was also used in an uncontrolled study with participants in an educational programme for close relatives of persons with borderline personality disorder, Family Connections (FC), which includes components of mindfulness training. The FC participants were found to (a) score lower than a comparison group on Act with Awareness and Accept without Judgment before treatment and (b) show significantly increased scores on Accept without Judgment after treatment.


Indirect evolution of social fitness inequalities and facultative social exploitation.
Microbial genotypes with similarly high proficiency at a cooperative behaviour in genetically pure groups often exhibit fitness inequalities caused by social interaction in mixed groups. Winning competitors in this scenario have been referred to as 'cheaters' in some studies. Such interaction-specific fitness inequalities, as well as social exploitation (in which interaction between genotypes increases absolute fitness), might evolve due to selection for competitiveness at the focal behaviour or might arise non-adaptively due to pleiotropy, hitchhiking or genetic drift. The bacterium Myxococcus xanthus sporulates during cooperative development of multicellular fruiting bodies. Using M. xanthus lineages that underwent experimental evolution in allopatry without selection on sporulation, we demonstrate that interaction-specific fitness inequalities and facultative social exploitation during development readily evolved indirectly among descendant lineages. Fitness inequalities between evolved genotypes were not caused by divergence in developmental speed, as faster-developing strains were not over-represented among competition winners. In competitions between ancestors and several evolved strains, all evolved genotypes produced more spores than the ancestors, including losers of evolved-versus-evolved competitions, indicating that adaptation in non-developmental contexts pleiotropically increased competitiveness for spore production. Overall, our results suggest that fitness inequalities caused by social interaction during cooperative processes may often evolve non-adaptively in natural populations.


Genome-wide association study of pancreatic cancer in Japanese population.
Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5x10(-7)) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30x10(-7), 3.30x10(-7), and 4.41x10(-7); located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer.


Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy.
In many common cancers, dissemination of secondary tumors via the lymph nodes poses the most significant threat to the affected individual. Metastatic cells often reach the lymph nodes by mimicking the molecular mechanisms used by hematopoietic cells to traffic to peripheral lymphoid organs. Therefore, we exploited naive T cell trafficking in order to chaperone an oncolytic virus to lymphoid organs harboring metastatic cells. Metastatic burden was initially reduced by viral oncolysis and was then eradicated, as tumor cell killing in the lymph node and spleen generated protective antitumor immunity. Lymph node purging of tumor cells was possible even in virus-immune mice. Adoptive transfer of normal T cells loaded with oncolytic virus into individuals with cancer would be technically easy to implement both to reduce the distribution of metastases and to vaccinate the affected individual in situ against micrometastatic disease. As such, this adoptive transfer could have a great therapeutic impact, in the adjuvant setting, on many different cancer types.


Radiological progression in established rheumatoid arthritis.
Radiographic progression in established rheumatoid arthritis (RA) gives an objective measure of anatomical damage that defines the course of the disease and the longterm effects of treatment. This review defines the rate of joint damage, progression in individual joints, and predictive factors. Six longitudinal prospective studies of 103-378 RA patients followed for up to 20 years show that initially patients had less than 3% maximum possible damage, this rose to 11% maximal damage by 5 years and over 40% by 20 years. The rate of progression changed from an initial rate of 1.6% maximal progression annually to a later rate of 2.0% annually. Between 1977 and 1998 5 prospective studies of 40-147 hospital-based RA cases seen within 12 months of developing RA showed 60-73% of cases developed one or more erosions in the hands and wrists. However a community-based cohort of early RA patients reported, more recently showed 41% of 335 cases developed erosions. There are marked differences between joints. The wrists show most damage and in one series of 103 cases, by 20 years 18% of wrists were completely destroyed and only 25% were nonerosive. The same series showed ankle joints are rarely involved; at 20 years only 7 patients had major abnormalities with minor changes in 17 cases. Rheumatoid factor (RF) positivity is the dominant predictor of erosive damage. In one survey of 439 cases who presented with inflammatory polyarthritis, patients with an initial high RF had over twice the radiographic progression of seronegative cases. A further 8 studies, which enrolled 1395 patients, all show a strong link between radiolographic damage and RF status. The other key clinical predictor is disease activity indicated by surrogate measures such as the C-reactive protein (CRP) level. Suppressing disease activity judged by CRP levels not only decreases the progression of joint damage, but also may reduce new joint involvement to a greater extent than progression in already damaged joints. New potential markers of damage such as anticyclic citrullinated peptide ELISA tests may further improve the identification of those RA patients most at risk of erosive damage and, by implication, most in need of suppressive therapy.


Dual stimuli-responsive supramolecular boron nitride with tunable physical properties for controlled drug delivery.
The new concept of modifying and tailoring the properties of existing two-dimensional (2D) nanomaterials by invoking the assembly of supramolecular networks upon association with a adenine-functionalized macromer (A-PPG) has significant potential to facilitate the development of highly water-dispersible few-layered 2D nanosheets. In this study, we propose that water-soluble A-PPG directly self-assembles into a long-period stacking-ordered lamellar structure over the surface of hexagonal boron nitride (BN) in aqueous solution, due to the efficient non-covalent interactions between A-PPG and BN nanosheets. The layer number of BN nanosheets can be easily tuned by altering the mass ratio of the A-PPG and BN blend, and the resulting exfoliated nanosheets also exhibit excellent temperature/pH-responsive behavior, biocompatibility and extremely high drug-loading capacity (up to 36.2%), features that are highly desirable yet exceedingly rare in traditional 2D nanomaterials. Importantly, in vitro drug release studies showed the drug-loaded nanosheets function as a stable nanocarrier with excellent stability and drug entrapment under normal physiological conditions. Increasing the environmental temperature to 40 °C or decreasing the pH to 5.5 triggered rapid release of the encapsulated drug from the drug-loaded nanosheets, suggesting this newly developed material has potential as a novel multi-responsive 2D nanocarrier to safely deliver drugs and effectively facilitate controlled drug release under specific microenvironmental conditions. This study provides new insight towards the promising application of this system in controlled release drug delivery systems.


Unicameral bone cyst of the humeral head: arthroscopic curettage and bone grafting.
Arthroscopic surgery has improved greatly over the past decade. Treatment of various juxta-articular disorders around the shoulder have benefited from endoscopic approaches. Cystic lesions of the shoulder on the scapular side have been treated in this way. This article describes a case of a 29-year-old patient with a unicameral bone cyst on the posterior aspect of the humeral head. Arthroscopic visualization using an accessory posteroinferior portal localized the cyst through the bare area of the humeral head. A cannulated burr was used to create an opening through the cortical wall between the cyst and the joint, and a careful curettage was performed. The cavity was filled with a demineralized bone matrix enriched with autologous blood packed into an arthroscopic cannula and delivered through the accessory portal. The patient reported pain relief immediately postoperatively and at follow-up. This case demonstrates the feasibility of arthroscopic treatment of a simple bone cyst of the humeral head. We believe that the knowledge of the juxta-articular anatomy allows the applications of scope-assisted procedures to be expanded, maximizing the results of a technique that allows a shorter recovery and less painful rehabilitation.


Mobile telemonitoring for achieving tighter targets of blood pressure control in patients with complicated diabetes: a pilot study.
Hypertension is a major risk factor for the long-term complications of diabetes. Mobile, self-measurement of blood pressure is emerging as a method to manage blood pressure in general, but its impact in patients with diabetes is unclear. We randomized 137 patients with diabetes and hypertension to either mobile telemonitoring (n = 72) or usual care (n = 65). Clinic blood pressure was recorded at baseline and after 6 months. Patients in the intervention arm transmitted weekly blood pressure readings wirelessly, using adapted sensors via mobile phones to a central server. Clinicians received the data in real-time and using a web-based application provided management advice to the patient and their physicians. Systolic blood pressure fell significantly in the patients in the intervention group (mean [95% confidence interval], -6.5 [-0.8 to -12.2] mm Hg; P = 0.027) and remained unchanged in the control group (2.1 [9.3 to -5.0] mm Hg; P = 0.57). Patients within the intervention arm of African origin seemed to benefit more from the intervention. In addition, those who achieved a systolic blood pressure of <120 mm Hg had lower average blood sugars than those with higher readings (7.8 [SD 1.6] vs. 8.9 [SD 2.2] mmol/L; P = 0.02). In patients with diabetes, mobile telemonitoring has potential for delivering intensified care to improve blood pressure control, and its use may be associated with reduced exposure to hyperglycemia.


Quantifying the effect of dobutamine stress on myocardial Pi and pH in healthy volunteers: A 31 P MRS study at 7T.
Phosphorus spectroscopy (31 P-MRS) is a proven method to probe cardiac energetics. Studies typically report the phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio. We focus on another 31 P signal: inorganic phosphate (Pi), whose chemical shift allows computation of myocardial pH, with Pi/PCr providing additional insight into cardiac energetics. Pi is often obscured by signals from blood 2,3-diphosphoglycerate (2,3-DPG). We introduce a method to quantify Pi in 14 min without hindrance from 2,3-DPG. Using a 31 P stimulated echo acquisition mode (STEAM) sequence at 7 Tesla that inherently suppresses signal from 2,3-DPG, the Pi peak was cleanly resolved. Resting state UTE-chemical shift imaging (PCr/ATP) and STEAM 31 P-MRS (Pi/PCr, pH) were undertaken in 23 healthy controls; pH and Pi/PCr were subsequently recorded during dobutamine infusion. We achieved a clean Pi signal both at rest and stress with good 2,3-DPG suppression. Repeatability coefficient (8 subjects) for Pi/PCr was 0.036 and 0.12 for pH. We report myocardial Pi/PCr and pH at rest and during catecholamine stress in healthy controls. Pi/PCr was maintained during stress (0.098 ± 0.031 [rest] vs. 0.098 ± 0.031 [stress] P = .95); similarly, pH did not change (7.09 ± 0.07 [rest] vs. 7.08 ± 0.11 [stress] P = .81). Feasibility for patient studies was subsequently successfully demonstrated in a patient with cardiomyopathy. We introduced a method that can resolve Pi using 7 Tesla STEAM 31 P-MRS. We demonstrate the stability of Pi/PCr and myocardial pH in volunteers at rest and during catecholamine stress. This protocol is feasible in patients and potentially of use for studying pathological myocardial energetics.


The impact of quality on hospital choice. Which information affects patients' behavior for colorectal resection or knee replacement?
Quality competition among hospitals, induced by patients freely choosing their hospital in a price regulated market, can only be realized if quality differences between hospitals are transparent, understandable, and thus influence patients' hospital choice. We use data from ~145,000 German patients and ~ 900 hospitals for colorectal resections and knee replacements to investigate whether patients value quality and specialization when choosing their hospital. Using a random utility choice model, we estimate patients' marginal utilities, willingness to travel and change in hospital demand for quality improvements. Patients respond to service quality and specialization and thus, quality competition seems to be present. Colorectal resection patients are willing to travel longer for more specialized hospitals (+9% for procedure volume, +9% for certification). Knee replacement patients travel longer for hospitals with better service quality (+6%) and higher procedure volume (+12%). However, clinical quality indicators, often difficult to access and interpret, barely play a role in patients' hospital choice. Furthermore, we find that competition on quality for colorectal resection is rather local, whereas for knee replacement we observe regional competition patterns.


Involvement of semiquinone radicals in the in vitro cytotoxicity of cigarette mainstream smoke.
Free radicals in cigarette smoke have attracted a great deal of attention because they are hypothesized to be responsible in part for several of the pathologies related to smoking. Hydroquinone, catechol, and their methyl-substituted derivatives are abundant in the particulate phase of cigarette smoke, and they are known precursors of semiquinone radicals. In this study, the in vitro cytotoxicity of these dihydroxybenzenes was determined using the neutral red uptake (NRU) assay, and their radical-forming capacity was determined by electron paramagnetic resonance (EPR). All of the dihydroxybenzenes studied were found to generate appreciable amounts of semiquinone radicals when dissolved in the cell culture medium employed in the NRU assay. Hydroquinone exhibited by far the highest capacity to form semiquinone radicals at physiological pH, even though it is not the most cytotoxic dihydroxybenzene. Methyl-substituted dihydroxybenzenes were found to be more cytotoxic than either hydroquinone or catechol. The formation of semiquinone radicals via auto-oxidation of the dihydroxybenzenes was found to be dependent on the reduction potential of the corresponding quinone/semiquinone radical redox couple. The capacity to generate semiquinone radicals was found to be insufficient to explain the variance in the cytotoxicity among the dihydroxybenzenes in our study; consequently, other mechanisms of toxicity must also be involved. The observed interactions between 2,6-dimethylhydroquinone and hydroquinone in the cytotoxicity assay and EPR analysis suggest that care needs to be taken when the bioactivity of cigarette smoke constituents is evaluated, i.e., the effect of the cigarette smoke complex matrix on the activity of the single constituent studied must be taken into consideration.


The race concept in six regions: variation without consensus.
Race, once the central concept in physical anthropology worldwide, now varies in the degree of support it receives in different regions. We present the currently available information on the status of the concept in the United States, the Spanish language areas, Poland, Europe, Russia, and China. Rejection of race ranges from high to low with the highest rejection occurring among anthropologists in the United States (and Canada). Rejection of race is moderate in Europe, sizeable in Poland and Cuba, and lowest in Russia and China. A discussion on the scientific and contextual reasons influencing these variations is presented. The tension between scientific evidence and social influences varies from region to region. The methods used in the studies reported here included questionnaires and content analysis. Response rates to questionnaires were often around 50 percent (with exception of the Polish studies). We discuss reasons for the low rates. Although a uniform method of data gathering is desirable, it may not suit scientists working in different traditions of theory and research. We conclude that it is once again timely to discuss the race concept in international meetings where all scientific and political changes occurring throughout the world in recent past decades are taken into account.


Effect of verapamil and of extracellular Ca and Na on contraction frequency of cultured heart cells.
Monolayer cultures of myocardial cells were prepared by trypsin dispersion of neonatal rat ventricles. The cells were cultured for 4-5 days by which time a synchronously contracting monolayer of some 1.0 x 10(6) cells per 6-cm diam petri dish had formed. The contraction frequency and Na influx of the cells were unaffected by tetrodotoxin (2 x 10(-5) mg/ml) but both were markedly reduced by the addition of verapamil (10(-9) M to 10(-5) M). The effect of verapamil on both parameters occurred very rapidly. Although unresponsive to change in [Ca]0 between 0.3 mM and 3.0 mM, the contraction frequency of the cells declined rapidly as the [Ca]0 was reduced below 0.3 mM. On the other hand the beating rate of the cells was linearly related to [Na]0 below 40 mM the cells ceased to contract. It is therefore apparent that both [Ca]0 and [Na]0 contribute to the maintenance of the contraction frequency of cultured myocardial cells, but the latter is by far the more important. There also appeared to be, under all conditions, a close relationship between verapamilsensitive Na influx and contraction frequency. For the greater part this relationship was linear although at higher Na influx values it appeared to show evidence of saturation.


When Winners Become Losers: Predicted Nonlinear Responses of Arctic Birds to Increasing Woody Vegetation.
Climate change is facilitating rapid changes in the composition and distribution of vegetation at northern latitudes, raising questions about the responses of wildlife that rely on arctic ecosystems. One widely observed change occurring in arctic tundra ecosystems is an increasing dominance of deciduous shrub vegetation. Our goals were to examine the tolerance of arctic-nesting bird species to existing gradients of vegetation along the boreal forest-tundra ecotone, to predict the abundance of species across different heights and densities of shrubs, and to identify species that will be most or least responsive to ongoing expansion of shrubs in tundra ecosystems. We conducted 1,208 point counts on 12 study blocks from 2012-2014 in northwestern Alaska, using repeated surveys to account for imperfect detection of birds. We considered the importance of shrub height, density of low and tall shrubs (i.e. shrubs >0.5 m tall), percent of ground cover attributed to shrubs (including dwarf shrubs <0.5 m tall), and percent of herbaceous plant cover in predicting bird abundance. Among 17 species considered, only gray-cheeked thrush (Catharus minimus) abundance was associated with the highest values of all shrub metrics in its top predictive model. All other species either declined in abundance in response to one or more shrub metrics or reached a threshold where further increases in shrubs did not contribute to greater abundance. In many instances the relationship between avian abundance and shrubs was nonlinear, with predicted abundance peaking at moderate values of the covariate, then declining at high values. In particular, a large number of species were responsive to increasing values of average shrub height with six species having highest abundance at near-zero values of shrub height and abundance of four other species decreasing once heights reached moderate values (≤ 33 cm). Our findings suggest that increases in shrub cover and density will negatively affect abundance of only a few bird species and may potentially be beneficial for many others. As shrub height increases further, however, a considerable number of tundra bird species will likely find habitat increasingly unsuitable.


The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory.
The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field.


Abdominal aortic coarctation: surgical treatment of 53 patients with a thoracoabdominal bypass, patch aortoplasty, or interposition aortoaortic graft.
Abdominal aortic coarctation is uncommon and often complicated with coexisting splanchnic and renal artery occlusive disease. This study was undertaken to define the clinical and anatomic characteristics of this entity, as well as the technical issues and outcomes of its operative treatment. Fifty-three patients, 34 males and 19 females, underwent surgical treatment of abdominal aortic coarctations from 1963-2008 at the University of Michigan. Patient ages in years ranged from 2-4 (n = 4), 5-8 (n = 17), 9-14 (n = 16), 15-20 (n = 11) and 25-49 (n = 5). The mean age was 11.9 years. Developmental disease (n = 48), inflammatory aortitis (n = 4), and iatrogenic trauma (n = 1) were suspected etiologies. Aortic coarctations were suprarenal (n = 37), intrarenal (n = 12), or infrarenal (n = 4). Patients often had coexisting occlusive disease of the splanchnic (n = 33) and renal (n = 46) arteries. Major clinical manifestations included: aortic and renal artery-related secondary hypertension (n = 50), symptomatic lower extremity ischemia (n = 3), and intestinal angina (n = 3). Primary aortic reconstructive procedures included: thoracoabdominal bypass (n = 26), patch aortoplasty (n = 24), or an aortoaortic interposition graft (n = 3). Primary splanchnic (n = 19) or renal (n = 47) arterial reconstructions were performed as simultaneous (n = 45) or staged (n = 13) procedures in relation to the aortic surgery. Benefits existed regarding improved control of hypertension (n = 46), as well as elimination of extremity ischemia (n = 3) and mesenteric angina (n = 3). Secondary renal or splanchnic arterial reoperations (n = 8) were performed without mortality 5 days to 12 years postoperative for failed primary procedures. Secondary aortic procedures, 5 to 14 years postoperative, were performed for patch aortoplasties that became stenotic (n = 2) or aneurysmal (n = 1), and when thoracoabdominal bypasses developed an anastomotic narrowing (n = 1) or proved inadequate in size with patient growth (n = 1). No perioperative mortality accompanied either the primary or secondary aortic reconstructive procedures. Abdominal aortic coarctation represents a complex vascular disease. Individualized treatment changed little over the period of study, remaining dependent on the pattern of anatomic lesions, patient age, and anticipated growth potential. This experience documented salutary outcomes exceeding 90% following carefully performed operative therapy.


Corporate Investors Increased Common Ownership In Hospitals And The Postacute Care And Hospice Sectors.
The sharing of investors across firms is a new antitrust focus because of its potential negative effects on competition. Historically, the ability to track common investors across the continuum of health care providers has been limited. Thus, little is known about common investor ownership structures that might exist across health care delivery systems and how these linkages have evolved over time. We used data from the Provider Enrollment, Chain, and Ownership System of the Centers for Medicare and Medicaid Services to identify common investor ownership linkages across the acute care, postacute care, and hospice sectors within the same geographic markets. To our knowledge, this study provides the first description of common investor ownership trends in these sectors. We found that the percentage of acute care hospitals having common investor ties to the postacute or hospice sectors increased from 24.6 percent in 2005 to 48.9 percent in 2015. These changes have important implications for antitrust, payment, and regulatory policies.


Psychometric assessment of the short-form Child Perceptions Questionnaire: an international collaborative study.
To examine the factor structure and other psychometric characteristics of the most commonly used child oral-health-related quality-of-life (OHRQoL) measure (the 16-item short-form CPQ11-14 ) in a large number of children (N = 5804) from different settings and who had a range of caries experience and associated impacts. Secondary data analyses used subnational epidemiological samples of 11- to 14-year-olds in Australia (N = 372), New Zealand (three samples: 352, 202, 429), Brunei (423), Cambodia (244), Hong Kong (542), Malaysia (439), Thailand (220, 325), England (88, 374), Germany (1055), Mexico (335) and Brazil (404). Confirmatory factor analysis (CFA) was used to examine the factor structure of the CPQ11-14 across the combined sample and within four regions (Australia/NZ, Asia, UK/Europe and Latin America). Item impact and internal reliability analysis were also conducted. Caries experience varied, with mean DMFT scores ranging from 0.5 in the Malaysian sample to 3.4 in one New Zealand sample. Even more variation was noted in the proportion reporting only fair or poor oral health; this was highest in the Cambodian and Mexican samples and lowest in the German sample and one New Zealand sample. One in 10 reported that their oral health had a marked impact on their life overall. The CFA across all samples revealed two factors with eigenvalues greater than 1. The first involved all items in the oral symptoms and functional limitations subscales; the second involved all emotional well-being and social well-being items. The first was designated the 'symptoms/function' subscale, and the second was designated the 'well-being' subscale. Cronbach's alpha scores were 0.72 and 0.84, respectively. The symptoms/function subscale contained more of the items with greater impact, with the item 'Food stuck in between your teeth' having greatest impact; in the well-being subscale, the 'Felt shy or embarrassed' item had the greatest impact. Repeating the analyses by world region gave similar findings. The CPQ11-14 performed well cross-sectionally in the largest analysis of the scale in the literature to date, with robust and mostly consistent psychometric characteristics, albeit with two underlying factors (rather than the originally hypothesized four-factor structure). It appears to be a sound, robust measure which should be useful for research, practice and policy.


Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion].
This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 μg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 μg/dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.


Dynamics of a feline virus with two transmission modes within exponentially growing host populations.
Feline panleucopenia virus (FPLV) was introduced in 1977 on Marion Island (in the southern Indian Ocean) with the aim of eradicating the cat population and provoked a huge decrease in the host population within six years. The virus can be transmitted either directly through contacts between infected and healthy cats or indirectly between a healthy cat and the contaminated environment: a specific feature of the virus is its high rate of survival outside the host. In this paper, a model was designed in order to take these two modes of transmission into account. The results showed that a mass-action incidence assumption was more appropriate than a proportionate mixing one in describing the dynamics of direct transmission. Under certain conditions the virus was able to control the host population at a low density. The indirect transmission acted as a reservoir supplying the host population with a low but sufficient density of infected individuals which allowed the virus to persist. The dynamics of the infection were more affected by the demographic parameters of the healthy hosts than by the epidemiological ones. Thus, demographic parameters should be precisely measured in field studies in order to obtain accurate predictions. The predicted results of our model were in good agreement with observations.


Multiple attractors in stage-structured population models with birth pulses.
In most models of population dynamics, increases in population due to birth are assumed to be time-independent, but many species reproduce only during a single period of the year. A single species stage-structured model with density-dependent maturation rate and birth pulse is formulated. Using the discrete dynamical system determined by its Poincaré map, we report a detailed study of the various dynamics, including (a) existence and stability of nonnegative equilibria, (b) nonunique dynamics, meaning that several attractors coexist, (c) basins of attraction (defined as the set of the initial conditions leading to a certain type of attractor), (d) supertransients, and (e) chaotic attractors. The occurrence of these complex dynamic behaviour is related to the fact that minor changes in parameter or initial values can strikingly change the dynamic behaviours of system. Further, it is shown that periodic birth pulse, in effect, provides a natural period or cyclicity that allows multiple oscillatory solutions in the continuous dynamical systems.


Emended Description of Litomosoides molossi (Nematoda: Onchocercidae) and First Records of Litomosoides Species Parasitizing Argentinean Bats.
: During a long-term study on biodiversity of bats in the Yungas and Entre Ríos provinces, 1,304 specimens of bats included in the families Noctilionidae, Phyllostomidae, Vespertilionidae, and Molossidae were collected and checked for filarioids. Litomosoides molossi Esslinger, 1973 was recovered from the thoracic and abdominal cavities of Molossus molossus (prevalence [P] = 6.4%); Litomosoides chandleri Esslinger, 1973 from Artibeus planirostris (P = 6.9%), Sturnira oporaphilum (P = 66.6%), Sturnira erythromos (P = 23.8%), Sturnira lilium (P = 7.2%), and Eumops perotis (P = 50%); and Litomosoides saltensis n. sp. was collected from Eptesicus furinalis (P = 1.7%). In this paper, we emend the description of L. molossi; describe a new species, Litomosoides saltensis n. sp., on the basis of 1 female specimen; and report for the first time L. molossi and L. chandleri parasitizing Argentinean bats, expanding the host and locality records. Litomosoides molossi exhibits a slender buccal capsule, with an anterior segment transparent, and the posterior chitinous portion displays 2 thickenings in the first third; possesses 1 dorsal prominent cephalic papilla and 4 labial papillae distributed around the mouth; cuticle with lateral punctuations all along the hypodermic chords in both sexes; and male with area rugosa and tail without cloacal papillae. In L. chandleri, the lateral punctuations are distributed on the posterior extremity of the body in both sexes. Litomosoides saltensis n. sp. displays a thick buccal capsule with a posterior segment well cuticularized, possessing 2 thickenings in the anterior half; 4 labial and 2 ventral cephalic papillae; a globular vulva located anterior to the esophagus-intestine junction; cuticle with lateral punctuations in the posterior extremity of the body; and tail with salient phasmids. We also provide a taxonomic key for the identification of the Litomosoides sp. of bat dwelling. Long-term studies and large sample sizes are needed to detect the presence of Litomosoides sp. in bats, in contrast to the findings in cricetid rodents, which seem to be more frequently collected.


Proteomic Approaches for the Discovery of Biofluid Biomarkers of Neurodegenerative Dementias.
Neurodegenerative dementias are highly complex disorders driven by vicious cycles of intersecting pathophysiologies. While most can be definitively diagnosed by the presence of disease-specific pathology in the brain at postmortem examination, clinical disease presentations often involve substantially overlapping cognitive, behavioral, and functional impairment profiles that hamper accurate diagnosis of the specific disease. As global demographics shift towards an aging population in developed countries, clinicians need more sensitive and specific diagnostic tools to appropriately diagnose, monitor, and treat neurodegenerative conditions. This review is intended as an overview of how modern proteomic techniques (liquid chromatography mass spectrometry (LC-MS/MS) and advanced capture-based technologies) may contribute to the discovery and establishment of better biofluid biomarkers for neurodegenerative disease, and the limitations of these techniques. The review highlights some of the more interesting technical innovations and common themes in the field but is not intended to be an exhaustive systematic review of studies to date. Finally, we discuss clear reporting principles that should be integrated into all studies going forward to ensure data is presented in sufficient detail to allow meaningful comparisons across studies.


Use of a patient preference predictor to help make medical decisions for incapacitated patients.
The standard approach to treatment decision making for incapacitated patients often fails to provide treatment consistent with the patient's preferences and values and places significant stress on surrogate decision makers. These shortcomings provide compelling reason to search for methods to improve current practice. Shared decision making between surrogates and clinicians has important advantages, but it does not provide a way to determine patients' treatment preferences. Hence, shared decision making leaves families with the stressful challenge of identifying the patient's preferred treatment option. To address this concern, the present paper proposes to incorporate the use of a "Patient Preference Predictor" (PPP) into the shared decision-making process between surrogates and clinicians. A PPP would predict which treatment option a given incapacitated patient would most likely prefer, based on the individual's characteristics and information on what treatment preferences are correlated with these characteristics. Use of a PPP is likely to increase the chances that incapacitated patients are treated consistent with their preferences and values and might reduce the stress and burden on their surrogates. Including a PPP in the shared decision-making process therefore has the potential to realize important ethical goals for making treatment decisions for incapacitated patients. The present paper justifies this approach on conceptual and normative grounds.